2025 AD Strategic Fund: APOE Biology in Alzheimer's (ABA) (ABA)

The Impact of the APOE Genotype on Primary Taupathies

How do certain gene variations of APOE impact a specific form of frontotemporal lobar dementia?

Alberto Serrano-Pozo, MD, PhD
Massachusetts General Hospital
Charlestown, MA - United States

Background

Frontotemporal lobar dementia (FTLD) is one of a group of brain diseases characterized by the early onset of dementia (occurring by one's 40s or 50s) along with changes in personality, emotions and difficulty in comprehending language. FTLD-tau is a subgroup of FTLD in which abnormal tau protein accumulates in the brain.

Research indicates that a gene implicated in Alzheimer’s, called apolipoprotein E (APOE), may also play a key role in FTLD-tau. The APOE gene codes for the ApoE protein, which is thought to play a role in processing lipids (fats), metabolism, and the brain’s immune system. There are several genetic variations of APOE, including APOE-e2, APOE-e3 and APOE-e4. 

In preliminary research, Dr. Serrano-Pozo and colleagues found that APOE-e4 may be associated with worse clinical outcomes in people with FTLD-tau, whereas APOE-e2 may have the opposite effect. This is similar to findings in Alzheimer’s.

Research Plan

Dr. Serrano-Pozo and colleagues will utilize data from the National Alzheimer's Coordinating Center (NACC). Within this dataset, they have identified 716 participants who had FTLD-Tau and had cognitive data, brain tissue samples, as well as APOE genotyping, among other clinical data collected. The researchers will use mathematical modeling to determine links between APOE genes and clinical outcomes, markers of brain changes, and age and rate of decline. 

Additionally, they will use an advanced sequencing technique called transcriptomics to determine what genes are turned “on” or “off” in brain cells from people who did or did not have FTLD-Tau. This will allow them to determine how different APOE gene variations are turned “on” or “off” in FTLD-Tau, as well as identify other genes that are activated in the disease, suggesting that they may also be involved.

Impact

Results of this study could improve our understanding of the biological mechanisms that drive changes that are observed in FTLD-tau, especially those linked to APOE gene variations. It may also identify new potential targets for therapeutics.